Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-12-19
1997-10-07
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514618, 514620, 514621, 514381, 564156, 564162, 564169, 564165, 564170, 564172, 564173, 548253, C07C 6976, C07C23726, C07C23540
Patent
active
056749058
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/GB93/0101 filed Jun. 18, 1993. This invention relates to bicyclooctane and bicycloheptane derivatives, and more particularly to bicyclooctane and bicycloheptane derivatives which bind to cholecystokinin (CCK) and/or gastrin receptors. The invention also relates to methods for preparing such bicyclooctane and bicycloheptane derivatives and to compounds which are useful as intermediates in such methods.
Gastrin and the CCK's are structurally-related neuropeptides which exist in gastrointestinal tissue and in the CNS (see Mutt V., Gastrointestinal Hormones, Glass G. B. J., ed., Raven Press, N.Y., p 169 and Nisson G., ibid, p. 127).
Gastrin is one of the three primary stimulants of gastric acid secretion. Several forms of gastrin are found including 34-, 17-, and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe--NH.sub.2) which is reported in the literature to have full pharmacological activity (see Tracey H. J. and Gregory R. A., Nature (London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH2) in an attempt to elucidate the relationship between structure and activity.
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal motility, gall bladder contraction, pancreatic enzyme secretion, and are known to have a trophic action on the pancreas. They also inhibit gastric emptying and have various effects in the CNS.
Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as antagonists of the natural peptides.
A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which lowered gastrin activity is desirable. The hormone has also been shown to have a trophic action on cells in the stomach and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach.
Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa, and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (e.g. morphine) analgesia, and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCK.sub.B receptors) have been claimed to possess anxiolytic activity.
According to the present invention, medicaments for counteracting an effect of cholecystokinin or gastrin in a patient are prepared using a compound of the formula ##STR2## wherein A is selected from ##STR3## and B is selected from ##STR4## (provided that A is not ##STR5## when B is ##STR6## , and A is not ##STR7## when B is ##STR8## wherein W is a carbonyl, sulphonyl or sulphinyl group, and X is a carbonyl, sulphonyl or sulphinyl group or --C(O)--CH.sub.2 -- (in which the carbonyl group is bonded to Y), provided that at least one of W and X contains carbonyl C.sub.1 to C.sub.15 hydrocarbyl, up to two carbon atoms of the hydrocarbyl moiety optionally being replaced by a nitrogen, oxygen or sulphur atom provided that Y does not contain a --O--O-- group, and R.sub.10 is H, C.sub.1 to C.sub.3 alkyl, carboxymethyl or esterified carboxymethyl), phenyl, benzyl or substituted benzyl; ##STR9## wherein Q is H, C.sub.1 to C.sub.5 hydrocarbyl, or -R.sub.12 -U, wherein R.sub.12 is a bond or C.sub.1 to C.sub.3 alkylene and U is aryl, substituted aryl, heterocyclic, or substituted heterocyclic, ##STR10## wherein a is 0 or 1 and b is from 0 to 3, R.sub.1
REFERENCES:
patent: 3932512 (1976-01-01), Bharucha et al.
patent: 5141937 (1992-08-01), Siegel et al.
Kumar et al. "PMR Spectral Studies Of Diels-Alder Adducts: Anthracene-Crotonic Acid, Anthracene-Fumaric Acid & .beta.-Naphthol-Fumaric Acid", Indian J. Chem., vol. 23B:631-634, (1984).
Patent Abstract of Japan, vol. 014, No. 068, (C-686), Feb. 8, 1990, abstract of Kinoshita Seigo, "Production Of N-Substituted Norbornenedicarboximide Compound", Japanese 12 90 660, Nov. 22, 1989.
R. Bodmann et al., "Untersuchungen Zum Metabolismus Des Zentralen Analepticums Endomid Bei Der Ratte", Pharmazie, vol. 31:804-811, (1976).
Koch et al., "Thalidomid-Analoga", Monatshefte fur chemie, vol. 102:609-621, (1971).
Nagase, "Beitrage Zur Umlagerung Der Cyclischen Imidoester", Umlagerung der Cyclischen Imidoester, Bull. Chem. Soc. Jpn. vol. 37:1175-1180, (1964).
Waldmann, "Amino Acid Esters As Chiral Auziliaries in Lewis Acid Catalyzed Diels-Alder Reactions", Liebigs Ann. Chem., pp. 671-680, (1990).
Waldmann, "(S)-Proline Benzyl Ester As Chiral Auxiliary In Lewis Acid Catalyzed Asymmetric Diels-Alder Reactions", J. Org. Chem., vol. 53:6133-6136, (1988).
Koch et al. "Ueber Alkylierte Amide Bicyclischer Dicarbonsaeuren", Monatshefte fur Chemie, vol. 96:1928-1933, (1965).
Koch, "Ueber Alkylierte Amide Bicyclischer Dicarbonsaeuren", J. Amer. Chem. Soc., vol. 94:406-409, (1963). Journal of Chemistry, vol. 37, No. 11, pp. 232-2329, (1984).
Meek et al., "Some Diels-Alder Reactions Of Naphthacene", J. Org. Chem., vol. 32:69-72, (1967).
Weisz et al., Org. Mass Spectrom., 24(1), 37-40. Jan. 1989.
Masuyama et al., Chem. Express, 3(2), 127-30. Mar. 1988.
Ito et al., J. Am. Chem. Soc., 104(26), 7609-22. Dec. 1982.
Plieninger et al., Chem. Ber., 109(6), 2121-25. Mar. 1976.
Takeda et al., Chem. Ber., 95, 2344-53. Dec. 1962.
Davies Jonathan Michael Richard
Dunstone David John
Kalindjian Sarkis Barret
Low Caroline Minli Rachel
McDonald Iain Mair
Cross Laura R.
James Black Foundation Limited
Richter Johann
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